This invention relates to the field of tumor immunogenicity. More particularly, this invention, provides a method for increasing the expression of MHC class I and class II antigens, and costimulatory molecules by administration of inhibitors of histone deacetylation.
It is generally considered that tumorogenesis is related, in part, to failure of the immune system to reject spontaneously arising tumors by responding appropriately to tumor antigens. In a normal immune response, induction of T-lymphocytes is considered to be a critical initial step. Activation of T cells results in T cell proliferation, cytokine production by T cells and generation of T cell mediated effector functions. T cell activation requires an antigen-specific signal, which involves the participation of the antigenic peptide as well as major histocompatability complex (MHC) class I or class II proteins.
MHC class II molecules function primarily to present peptides derived from exogenous antigens to CD4 helper T cells. Effective presentation and activation of T cells requires a second signal delivered by costimulation molecules (Allison et al., 1995, Curr. Opin. Immunol. 7:682). The constitutive expression of MHC class II molecules is restricted to a few cell types, the antigen presenting cells (APCS) which include B lymphocytes, dendritic cells and some macrophages. However, many normal cells including epithelial cells, endothelial cells, astrocytes, resting T cells and some monocytes/macrophages express MHC class II after activation by various stimuli especially gamma-interferon (IFNxcex3; see Glimcher et al., 1992, Ann. Rev. Immunol., 10:13). Only a few cell types, including mature oligodendrocytes, sensory neurons, trophoblasts, and some tumor cells cannot be induced to express class II by IFNxcex3.
While a few tumor cells display nearly normal levels of cell surface MHC class II, most do not (Cabrera et al., 1995, J. Immunol., 41:398). In some class II negative tumor cells, the class II transactivator (CIITA) is non-inducible and these cells fail to transcribe mRNA for class II after treatment with IFNxcex3 but will, if transfected with CIITA. Also, genes encoding costimulatory molecules which are required for activation of T cells are not expressed by many tumor cells (Chen et al., 1994, JEM, 179:523). Although these data suggest that the expression of MHC genes and costimulatory molecules is altered in some tumors, it is not clear how their expression relates to tumor immunogenicity. Thus, there continues to be need to identify factors and methods by which tumor immunogenicity can be increased so as to make tumors more amenable to immunotherapy.
The present invention discloses a method for enhancing the cell surface expression of MHC antigens on tumor cells. It was observed that low concentrations of deacetylase inhibitors (DAIs) that produced little or no apoptosis, and maintain an essentially normal cell cycle, induced the expression of MHC class I and class II, and CD40.
Thus, an object of the present invention is to provide a method for increasing the immunogenicity of tumors by inhibitors of deacetylation.
Another object of the present invention is to induce the expression of MHC genes and other molecules of immunologic importance in antigen presentation and cell lysis on cells, by exposure to inhibitors of histone deacetylation.